Overall Abstract The overall goal of this SPORE in Myeloid Malignancies is to take advantage of our increased understanding of the genetic and molecular basis of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) to develop novel, effective therapeutic strategies for patients with these treatment-resistant neoplasms. The extensive scientific and clinical resources at the Dana-Farber/Harvard Cancer Center (DF/HCC) will be leveraged ? marshaling local expertise in cell and molecular biology, genetics, immunology, biostatistics, chemistry, murine models, and clinical trial development ? in order to perform innovative pre-clinical studies, to validate novel drug targets in patient cells, and to design and implement clinical trials that will eventually lead to improved outcomes for patients with myeloid malignancies. Each of the four Projects will promote detailed analysis of a promising new target by a combination of pre-clinical studies to optimize therapeutic development and early-stage clinical trials. Project 1 leverages recent exciting data from the laboratory of Dr. Scott Armstrong regarding the efficacy of targeting the MLL-menin interaction, which is essential for maintaining HOXA expression and maintenance of leukemia stem cells. Project 2 is based on the discovery by the Stegmaier laboratory that many cases of AML are dependent on SYK kinase activation, and that SYK activation causes chemotherapy resistance. Project 3 will examine the pre-clinical and clinical efficacy of a novel SF3B1 inhibitor, using an Sf3b1-mutant model developed by the Ebert laboratory, for the treatment MDS. Project 4 will examine the potential synergy of a highly effective vaccine with a potent immunologic checkpoint inhibitor for the treatment of AML. The Cores have been designed to support all projects in translational research. The laboratory and clinical research components of each project will interface with Core 1 for statistical guidance in both experimental design and the interpretation of results. Core 2 will provide biospecimens banking for the samples produced by all projects in the course of clinical trials; these samples will be used for the generation of primagrafts in immunodeficient mice. Samples from the biospecimens bank as well as xenograft samples will, in turn, be available for use by the PI's of all projects. Core 3 will work with the clinical trials in each project for correlative studies. Ultimately, the proposed studies promise to improve the therapy of chemotherapy-resistant AML and splicing factor-mutant MDS, as well as developing an improved immunotherapeutic strategy for AML.